Many triazole derivatives are antimycotic agents which are widely used in the treatment of mycosis.
A number of patents report the synthesis of efinaconazole starting form 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole and 4-methylenepiperidine free base or hydrochloride.
WO9426734 reports the synthesis of efinaconazole starting from the intermediate 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole, whose epoxytriazole ring is opened by the use of a large excess (10 equivalents) of methylenepiperidine in the form of a hydrochloride suitably neutralised. Said opening reaction takes place in the absence of reaction-promoting metal species; the product is obtained in a yield of 54%.
The disadvantages of said process are the use of a large excess of methylenepiperidine (which is relatively expensive), and low yields. A further drawback is that methylenepiperidine free base is not commercially available, whereas the hydrochloride is available.
WO2012029836 discloses a process for obtaining efinaconazole starting from 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole and methylenepiperidine hydrobromide salt in the presence of metal hydroxides such as lithium, sodium, calcium or strontium hydroxide; methylenepiperidine is used in much smaller amounts (1.5 equivalents) than the large excess used in WO9426734. The end product is obtained in a yield of 87%. Although efinaconazole is obtained in higher yields, the use of metal hydroxides (lithium, sodium, calcium and strontium) generates, in the release of methylenepiperidine base, the formation of water which reduces the quality (the purity of the isolated product is about 95%) and the yield when the end product is isolated. The reason is that the water present in the reaction competes with methylenepiperidine in the epoxide ring opening, causing hydrolysis of the latter with a consequent loss of yield and quality of the finished product.
On the basis of the available information there is an evident need for a more efficient process for the industrial production of efinaconazole.